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WO2005048996A2 - Formes posologiques a liberation modifiee de relaxants des muscles du squelette - Google Patents

Formes posologiques a liberation modifiee de relaxants des muscles du squelette Download PDF

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Publication number
WO2005048996A2
WO2005048996A2 PCT/US2004/037266 US2004037266W WO2005048996A2 WO 2005048996 A2 WO2005048996 A2 WO 2005048996A2 US 2004037266 W US2004037266 W US 2004037266W WO 2005048996 A2 WO2005048996 A2 WO 2005048996A2
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Prior art keywords
dosage form
beads
pharmaceutical dosage
hours
active
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WO2005048996A3 (fr
Inventor
Gopi Venkatesh
James M. Clevenger
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Adare Pharma Solutions Inc
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Eurand America Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T29/00—Metal working
    • Y10T29/49—Method of mechanical manufacture
    • Y10T29/49826—Assembling or joining

Definitions

  • a major objective of developing and commercializing controlled release dosage forms for indications such as cardiovascular diseases, chronic pain, relief of muscle spasm and associated symptoms especially in the elderly is to deliver the drug so as to maintain the drug at therapeutically effective concentrations over an extended period of time, thereby enhancing patient compliance and therapeutic efficacy, thereby reducing both cost of treatment and side effects.
  • the patent is directed to a system for the controlled-rate release of active substances consisting of a deposit core comprising an active substance and at least one of (a) a polymeric material having a high degree of swelling on contact with water and a gellable polymeric material or (b) a single polymeric material having both swelling and gelling properties, and a support platform applied to the deposit core wherein the support platform consists of a water insoluble polymeric material.
  • U.S. Pat. Nos. 4,851,228 and No. 4,968,507 both to Zentner et al., assigned to Merck & Company, refer to a multi-particulate osmotic pump for the controlled release of a pharmaceutically active agent, each osmotic pump element consisting essentially of a core containing an active agent and a rate controlling water insoluble wall comprising a semi-permeable polymer and at least one pH insensitive pore forming additive dispersed throughout the wall.
  • 4,882,167 to Jang are directed to a compressed product containing an active produced by dry blending with a matrix combination of a hydrophobic polymer (e.g. ethylcellulose) and a wax, fatty acid, neutral lipid or combination thereof.
  • a hydrophobic polymer e.g. ethylcellulose
  • U.S. Pat. No. 4,996,047 to Kelleher, assigned to Richardson-Vicks, is directed to an oral pharmaceutical composition in unit dosage form of ion-exchange resin particles having a pharmacologically active drug bound thereto wherein the drug-resin complex particles have been coated with a water-impermeable diffusion barrier to provide controlled release of the active drug.
  • U.S. Pat. No. 4,996,047 to Kelleher, assigned to Richardson-Vicks is directed to an oral pharmaceutical composition in unit dosage form of ion-exchange resin particles having a pharmacologically active drug bound thereto wherein the drug-resin complex particles have been coated with a water-impermeable diffusion barrier to provide controlled release of the active drug.
  • 5,120,548 to McClelland et al. is directed to a controlled release drug delivery device comprising a composition of a polymer which swells upon exposure to an aqueous environment, a plurality of controlled release swelling modulators, at least one active agent and either a water insoluble polymer coating surrounding the composition or a microporous wall surrounding the composition.
  • U.S. Pat. No. 5,350,584 to McClelland et al., assigned to Merck & Company relates to a process for the production of microcrystalline cellulose- free multiparticulates comprising a medicament and a charged resin. The resulting spheronized beads can be used in certain controlled release dosage forms.
  • U.S. Pat. No. 5,366,738 to Rork et al. is directed to a drug delivery device for controlled release of an active agent.
  • the drug delivery device includes a compressed core with an active agent and a polymer which forms gelatinous microscopic particles upon hydration and a water insoluble, water impermeable polymeric coating comprising a polymer and plasticizer which surrounds and adheres to the core.
  • U.S. Patent 5,582,838 to Rork et al. is related to a drug delivery device for the controlled release of a beneficial agent.
  • the drug delivery device includes a compressed core having at least two layers: at least one layer is a mixture of a beneficial agent and a polymer which forms microscopic polymer gel beads upon hydration and at least one outer layer comprises a polymer which forms microscopic polymer gel beads upon hydration.
  • a water insoluble, water impermeable coating is applied to the core and the coating has apertures exposing between about 5-75% of the core surface.
  • U.S. Patent No. 5,874,418 to Stella et al., assigned to Cydex is directed to a pharmaceutical composition comprising a carrier and a mixture of a sulfoalkyl ether- cyclodextrin and a therapeutic agent wherein a major portion of the therapeutic agent is not complexed to the sulfoalkyl ether-cyclodextrin derivative. Delayed, sustained or controlled release formulations are also described wherein the pharmaceutical core is coated with a film coating comprising a file forming agent and a pore forming agent.
  • 5,882,682 to Rork et al. is directed to a drug delivery process including the steps of preparing a uniform mixture of a polymer which forms gelatinous microscopic particles upon hydration, the beneficial agent and other excipients used in the preparation of the core; compressing the mixture into cores; coating the entire core with a water insoluble, water impermeable polymeric coating including a polymer and a plasticizer; and forming apertures through the coating.
  • U.S. Patent No. 5,952,451 to Zhao assigned to Guilford Pharmaceuticals is directed to a process for preparing high molecular weight poly(phosphoester) compositions comprising a biologically active substance and a poly(phosphoester) and the high molecular weight compositions produced thereby.
  • the polymers so produced are useful in prolonged released drug delivery systems.
  • U.S. Patent No. 5,952,451 to Zhao assigned to Guilford Pharmaceuticals is directed to a process for preparing high molecular weight poly(phosphoester) compositions comprising a biologically active substance and a poly(phosphoester) and the high molecular weight compositions produced thereby.
  • the polymers so produced are useful in prolonged released drug delivery systems.
  • 6,004,582 to Faour et al. assigned to Laboratorios Phoenix U.S.A., is directed to a multi-layered osmotic device comprising a compressed core including a first active agent and an osmotic agent, a semi- permeable membrane surrounding the core and having a preformed passageway therein wherein the membrane is permeable to a fluid in the environment of use and substantially impermeable to the first active agent.
  • the semi-permeable membrane preferably consists essentially of cellulose acetate and poly(ethylene glycol).
  • the external coat can includes poly(vinylpyrrolidone) and poly (ethylene glycol) and can further includes materials such as HPMC, ethylcellulose, hydroxyl ethylcellulose, CMC, dimethylaminoethyl methacrylate-methacrylic acid ester copolymer, ethyl acrylate-methyl methacrylate copolymer, and combinations thereof.
  • HPMC poly(vinylpyrrolidone) and poly (ethylene glycol) and can further includes materials such as HPMC, ethylcellulose, hydroxyl ethylcellulose, CMC, dimethylaminoethyl methacrylate-methacrylic acid ester copolymer, ethyl acrylate-methyl methacrylate copolymer, and combinations thereof.
  • HPMC ethylcellulose
  • CMC dimethylaminoethyl methacrylate-methacrylic acid ester copolymer
  • WO 99/30671 to Ron is directed to an oral delivery vehicle including an aspected particle comprising a pharmaceutically active component and excipients wherein the vehicle is formulated to provide controlled delivery of the pharmaceutically active component.
  • the vehicle may further contain a coating to provide sustained drug delivery to the particle.
  • WO 98/53802 to Faour et al. (Laboratorios Phoenix USA), is directed to a multi-layered osmotic device that is capable of delivering a first active agent in an outer lamina to one environment of use and a second active agent in the core to another environment of use.
  • An erodible polymer coat between an internal semipermeable membrane and a second active agent-containing external coat comprises poly(vinylpyrrolidone)-vinyl acetate) copolymer.
  • the active agent in the core is delivered through a pore containing an erodible plug.
  • WO 98/18610 to Van Lengerich is directed to particles containing an active agent, which provide controlled release of the active ingredient without substantial destruction of the matrix material.
  • a release-rate controlling component is incorporated in a matrix to control the rate-release of the encapsulant from the particles.
  • a hydrophobic component or a high water binding capacity component may be used for extending the release time. Release properties may also be controlled by precoating the encapsulant and/or coating the particles with a film-forming component.
  • WO 98/06439 to Oedemoed, is directed to a composition comprising a biologically active agent encapsulated in a matrix comprising a polyether ester copolymer, such as polyethylene glycol terephthalate/ polybutylene-terephthalate copolymer.
  • a polyether ester copolymer such as polyethylene glycol terephthalate/ polybutylene-terephthalate copolymer.
  • the polyether ester copolymer protects the active agent from degradation and thereby facilitates the drug delivery.
  • Cyclobenzaprine hydrochloride a skeletal muscle relaxant
  • Flexeril IR (immediate release) tablets containing 10 mg of cyclobenzaprine HCl are administered three times a day to relieve skeletal muscle spasm of local origin without interfering with muscle function.
  • the oral administration thrice daily is an issue of patient compliance, especially with the elderly.
  • modified release skeletal muscle relaxant suitable for a single administration.
  • MR modified release
  • the present invention provides a modified release, multi-particulate dosage form of a skeletal muscle relaxant comprising one or more bead populations which provides an extended release profile of the active under in vitro conditions closely mimicking the profile simulated from pharmaco-kinetic modeling.
  • One of the bead populations is an ER (extended release) Bead population typically comprising a coating of a water insoluble polymer alone, or in combination with a water soluble polymer, applied onto active containing cores.
  • the active core of the dosage form of the present invention may comprise an inert particle such as a sugar sphere, or an acidic or alkaline buffer crystal, which is coated with a skeletal muscle relaxant such as cyclobenzaprine hydrochloride- containing film-forming formulation, preferably a water-soluble film forming composition.
  • the first coating formulation may contain, in addition to the active, a binder such as hydroxypropyl cellulose.
  • the drug layered beads may be coated with a protective seal coating of OP ADR Y® Clear to produce IR Beads.
  • the core particle may be formed by granulating and dry milling and/or by extrusion and spheronization of a pharmaceutical composition containing the active. The amount of drug in the core will depend on the dose required and typically varies from about 5 to about 60% by weight.
  • ER Beads can be produced by applying a functional membrane comprising a water insoluble polymer alone or in combination with a water soluble polymer onto IR Beads.
  • the capsule formulation for once a day, oral administration of a skeletal muscle relaxant prepared in accordance with the present invention comprises ER Beads containing the active substance and optionally LR Beads.
  • IR (immediate release) Beads allow immediate release of the active while ER Beads allow an extended release profile of the active over several hours.
  • such a capsule formulation provides for therapeutically effective plasma profiles over an extended period of time, thereby resulting in improved patient compliance.
  • a pharmaceutical dosage form of a skeletal muscle relaxant includes one or more bead populations and provides a modified release profile. At least one of the bead populations includes extended release (ER) beads wherein the ER beads include a core particle (IR (immediate release) bead) containing a skeletal muscle relaxant and an ER (extended release) coating comprising a water insoluble polymer surrounding the core.
  • ER extended release
  • the dosage form in accordance with certain embodiments, when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm) in 900 mL of 0.
  • IN HCl (or a suitable dissolution medium) at 37°C exhibits a drug release profile substantially corresponding to the following pattern: after 2 hours, no more than about 40% of the total active is released; after 4 hours, from about 40-65% of the total active is released; after 8 hours, from about 60-85% of the total active is released; and after 12 hours, from about 75- 85% of the total active is released.
  • the dosage form thereby provides a therapeutically effective plasma concentration over an extended period of time, typically over a period of 24 hours to treat muscle spasm associated with painful musculoskeletal conditions in humans.
  • Fig. 1 shows the proposed target release profile for cyclobenzaprine hydrochloride MR (modified release) capsules, 15 and 30 mg.
  • Fig. 2 shows the simulated Day 1 plasma level following dosing of 1x10 mg Flexeril® given 3 times a day and 1x30 mg cyclobenzaprine HCl MR capsule given once- daily.
  • Fig. 3 shows the drug release profiles for cyclobenzaprine HCl ER (extended release) beads of Example 2.
  • Fig. 4 compares the drug release profiles as a function of membrane coating of Example 3.
  • Fig. 5 shows the drug release profiles for cyclobenzaprine HCl ER beads of Example 3 stored in induction sealed HDPE bottles on accelerated stability.
  • Fig. 6 shows the drug release profiles for 30 mg cyclobenzaprine HCl MR capsules of Example 4.
  • Fig. 7 shows the plasma levels for cyclobenzaprine HCl MR capsules, 15 and 30 mg of Example 5.
  • the active core of the dosage form of the present invention may be comprised of an inert particle or an acidic or alkaline buffer crystal, which is coated with a drug- containing film-forming formulation and preferably a water-soluble film forming composition to form a water-soluble/dispersible particle.
  • the active may be prepared by granulating and milling and/or by extrusion and spheronization of a polymer composition containing the drug substance.
  • the amount of drug in the core will depend on the dose that is required, and typically varies from about 5 to 60 weight %.
  • the polymeric coating on the active core will be from about 4 to 20% based on the weight of the coated particle, depending on the type of release profile required and/or the polymers and coating solvents chosen. Those skilled in the art will be able to select an appropriate amount of drug for coating onto or incorporating into the core to achieve the desired dosage.
  • the inactive core may be a sugar sphere or a buffer crystal or an encapsulated buffer crystal such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc. which alters the microenvironment of the drug to facilitate its release.
  • the drug-containing particle may be coated with an extended release (ER) coating comprising a water insoluble polymer or a combination of a water insoluble polymer and a water soluble polymer to provide ER beads.
  • ER extended release
  • the water insoluble polymer and the water soluble polymer may be present at a weight ratio of from 100/0 to 65/35, more particularly from about 95/5 to 70/30, and still more particularly at a ratio of from about 85/15 to 75/25.
  • the extended release coating is applied in an amount necessary to provide the desired release profile.
  • the extended release coating typically comprises from about 1% to 15%, more particularly from about 7% to 12%, by weight of the coated beads.
  • the present invention also provides a method of making a modified release dosage form including a mixture of two bead populations, hi accordance with one embodiment, the method includes the steps of:
  • preparing a drug-containing core by coating an inert particle such as a nonpareil seed, an acidic buffer crystal or an alkaline buffer crystal with a drug and a polymeric binder or by granulation and milling or by extrusion/spheronization to form an immediate release (TR) bead; 2. coating the TR bead with a plasticized water-insoluble polymer alone such as ethylcellulose or in combination with a water soluble polymer such as hydroxypropylmethylcellulose to form an Extended Release (ER) bead; 3. filling into hard gelatin capsules ER Beads alone or in combination with TR Beads at a proper ratio to produce MR (modified release) capsules providing the desired release profile.
  • an inert particle such as a nonpareil seed, an acidic buffer crystal or an alkaline buffer crystal with a drug and a polymeric binder or by granulation and milling or by extrusion/spheronization to form an immediate release (TR) bea
  • TR beads when tested in accordance with the following procedure release at least about 70%, more specifically at least about 90% of the active within 30 minutes.
  • Dissolution Apparatus USP Apparatus 2 (Paddles at 50 rpm), dissolution medium: 900 mL 0.1N HCl (or a suitable dissolution medium) at 37°C and Drug Release determination by HPLC).
  • An aqueous or a pharmaceutically acceptable solvent medium may be used for preparing drug-containing core particles.
  • the type of film forming binder that is used to bind the drug to the inert sugar sphere is not critical but usually water soluble, alcohol soluble or acetone/water soluble binders are used.
  • Binders such as polyvinylpyrrolidone (PVP), polyethylene oxide, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polysaccharides such as dextran, corn starch may be used at concentrations from about 0.5 to 5 weight %, although other concentrations may be useful.
  • the drug substance may be present in this coating formulation in the solution form or may be dispersed at a solid content up to about 35 weight % depending on the viscosity of the coating formulation.
  • the drug substance optionally a binder such as PVP, a dissolution rate controlling polymer (if used), and optionally other pharmaceutically acceptable excipients are blended together in a planetary mixer or a high shear granulator such as Fielder and granulated by adding/spraying a granulating fluid such as water or alcohol.
  • the wet mass can be extruded and spheronized to produce spherical particles (beads) using an extruder/marumerizer.
  • the drug load could be as high as 90% by weight based on the total weight of the extruded/spheronized core.
  • Representative muscle relaxants include cyclobenzaprine, dantrolene sodium, methocarbamol, metaxalone, carisoprodol, diazepam and pharmaceutically acceptable salts or derivatives thereof.
  • Cyclobenzaprine hydrochloride is a particularly useful muscle relaxant.
  • the useful muscle relaxants include the base, pharmaceutically acceptable salts thereof such as hydrochloride, stereoisomers thereof and mixtures thereof.
  • water insoluble polymers useful in the ER coating include ethylcellulose powder or an aqueous dispersion (such as AQUACOAT ® ECD-30), cellulose acetate, polyvinyl acetate (Kollicoat SR#30D from BASF), neutral copolymers based on ethyl acrylate and methylmethacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups such as Eudragit NE, RS and RS30D, RL or RL30D and the like.
  • water soluble polymers useful herein include low molecular weight hydroxypropyl methylcellulose (HPMC), methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyethylene glycol (PEG of molecular weight > 3000) and mixtures thereof.
  • HPMC low molecular weight hydroxypropyl methylcellulose
  • methylcellulose methylcellulose
  • hydroxypropylcellulose polyvinylpyrrolidone
  • PEG polyethylene glycol
  • the extended release coating will typically be applied at a thickness ranging from about 1 weight % up to 15 weight % depending on the solubility of the active in water and the solvent or latex suspension based coating formulation used.
  • the coating compositions used in forming the membranes are usually plasticized.
  • plasticizers that may be used to plasticize the membranes include triacetin, tributyl citrate, triethyl citrate, acetyl tri-n-butyl citrate diethyl phthalate, polyethylene glycol, polypropylene glycol, castor oil, dibutyl sebacate, acetylated monoglycerides and the like or mixtures thereof.
  • the plasticizer may comprise about 3 to 30 wt.% and more typically about 10 to 25 wt.% based on the polymer.
  • the type of plasticizer and its content depends on the polymer or polymers, nature of the coating system (e.g., aqueous or solvent based, solution or dispersion based and the total solids).
  • HPMC hydroxypropyl methylcellulose
  • HPC hydroxypropylcellulose
  • membrane coatings can be applied to the core using any of the coating techniques commonly used in the pharmaceutical industry, but fluid bed coating is particularly useful.
  • the present invention is applied to multi-dose forms, i.e., drug products in the form of multi-particulate dosage forms (pellets, beads, granules or mini-tablets) or in other forms suitable for oral administration. As used herein, these terms are used interchangeably to refer to multi-particulate dosage forms.
  • the invention also provides a method of making an extended release dosage form which includes a mixture of two or more bead populations.
  • the method includes the steps of: (a) coating an inert particle such as a non-pareil seed, an acidic buffer crystal or an alkaline buffer crystal with a drug and polymeric binder to form an active drug particle (TR beads), which may be present in the unit dosage form to act as a bolus dose; (b) coating the active drug particle with a solution or suspension of a water insoluble polymer or a mixture of water soluble and water insoluble polymers to form an extended release coated drug particle (ER beads); (c) filling into a hard gelatin capsule ER beads alone and optionally, in combination with TR beads at a proper ratio ranging from 95/5 to 70/30 (ER beads/TR beads) to produce a MR (modified release) capsule exhibiting a target drug release profile.
  • an inert particle such as a non-pareil seed, an acidic buffer crystal or an alkaline buffer crystal with
  • Cyclobenzaprine is well absorbed after oral administration, but there is a large intersubject variation in plasma levels. It is eliminated quite slowly with a half-life as long as one to three days.
  • the present treatment regimen of 10 mg three times daily is an issue of patient compliance, especially the elderly.
  • a modified release dosage form (capsule) was designed with a release profile shown in Figure 1. To determine if this is the proper release profile, the pharmacokinetics data of cyclobenzaprine following a single dose of 10 mg Flexeril ® tablets administered 3 times a day was taken from the literature. A pharmacokinetic model was developed from this data using WinNonlinTM Version 1.5.
  • Cyclobenzaprine Hydrochloride (1,200 g) was slowly added to an aqueous solution of polyvinylpyrrolidone such as Povidone USP (K-29/32, 80 g) and mixed well.
  • # 25-30 mesh sugar spheres (2,640 g) were coated with the drug solution in a Glatt fluid bed coater, equipped with a 9" bottom spray Wurster insert to provide TR beads with a coating weight of about 9%.
  • the drug containing particles were dried, and a seal coat of OPADRY ® Clear (2% w/w) was first applied and dried in the Glatt fluid bed unit as a precautionary measure to drive off excessive surface moisture.
  • composition and batch quantities of the IR Beads were given in 5 to 10 kg. Following the second coating process the IR Beads were passed through 14 and 25 mesh screens. Beads remaining on the 14- mesh screen were discarded as oversized beads and beads passing through the 25-mesh screen were discarded as undersized beads.
  • the next step in the process was to apply an extended release polymer membrane by spraying AQUACOAT ® ECD 30, an aqueous dispersion of ethylcellulose with dibutyl sebacate (76:24), onto the TR Beads for a weight gain of approximately 10%.
  • the same fluid bed equipment was used to produce ER (extended release) Beads by further coating the AQUACOAT ® coated beads with OPADRY ® Clear for a weight gain of 2% w/w prior to curing at 60°C in a conventional oven for a period of 24 hours.
  • the batch size was 5 to 10 kg.
  • the drug release profiles are shown in Fig. 3.
  • the figure also shows the drug release profiles from ER Beads stored in induction sealed HDPE bottles at 25°C/60%RH for 6 months.
  • Cyclobenzaprine Hydrochloride (2.5 kg) was dissolved in 50/50 acetone/purified water. 25-30 mesh Sugar spheres, (7.3 kg) were coated with the drug solution in a Glatt fluid bed coater, equipped with a 9" bottom spray Wurster insert. The drug containing particles were dried, and a seal coat of OPADRY® Clear (2% w/w) was first applied and dried in the Glatt fluid bed unit as a precautionary measure to drive off excessive surface moisture.
  • ethylcellulose Ethocel Premium Standard 10 cps
  • diethyl phthalate 910 g
  • the release rates of the ER Beads will vary depending upon the film weight of the ER coating.
  • One batch of IR Beads was coated for a final weight gain of 7% based on the weight of coated beads wherein samples of the ER Beads were removed during the ER coating process to yield beads with increasing coating weights.
  • Another batch was coated for 10%o weight gain and all the coated bead batches were cured at 60°C for 4 hours in a conventional oven.
  • Fig. 4 shows the relationship between the ER coating weights and the release rate of the finished ER coated Beads.
  • a batch was coated with a 7% ER coating and cured at 60°C for 4 hours. No changes were noted in the release rates, assay values or impurity levels after storage in HDPE bottles at 40°C/75% RH for a period of 6 months. The release rates for the samples are shown in Fig. 5.
  • the drug layering, seal coating, and ER Coating processes were scaled-up to Glatt GPCG 120 equipped with an 18" bottom spray Wurster insert (batch size: 80 kg for LR Beads and 85 kg for ER Beads).
  • the process parameters of each of the processes were optimized.
  • the drug layering solution (9%o weight gain), seal coating solution, and the ER coating solution (9% weight gain) were sprayed onto the sugar spheres or IR Beads while maintaining the product temperature between narrow limits. Following the seal or ER coating the beads were passed through 14 and 25 mesh screens discarding any beads remaining on the 14 mesh screen.
  • the ER Beads were also cured at 60°C for a period of 4 hours.
  • AUCo- ⁇ 68 refers to the area under the plasma concentration-time curve to the last measurable time point (168 hrs) calculated by the linear trapezoidal rule
  • AUCo- ⁇ refers to area under the concentration-time curve to infinity
  • C ma ⁇ refers to the maximum blood plasma concentration
  • T ma x refers to the time to maximum plasma levels of cyclobenzaprine.
  • the adjusted mean ratio of CMR 30 mg to CMR 15 mg was greater than about 2 for each of the AUCs and C max , specifically the calculated values were 2.42 for AUC 0 .i68 (pO.OOl), 2.286 for AUC 0- ⁇ (pO.OOl), and 2.424 for C ma ⁇ (pO.OOl). Overall, both CMR 15 mg and 30 mg were well tolerated during the study.
  • one aspect of the invention relates to a dosage fo ⁇ n containing cyclobenzaprine hydrochloride as a skeletal muscle relaxant wherein the pharmaceutical dosage form provides a maximum blood plasma concentration (C ma ⁇ ) within the range of about 80% to 125%) of about 20 ng/n L of cyclobenzaprine HCl, an AUCo- ⁇ 68 within the range of about 80% to 125% of about 740 ng-hr/mL and a T max within the range of about 80% to 125% of about 7 hours following oral administration of a single 30 mg cyclobenzaprine HCl MR Capsule.
  • C ma ⁇ maximum blood plasma concentration

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Abstract

L'invention concerne une forme posologique unitaire, par exemple une capsule ou autre forme semblable, permettant d'administrer dans le corps un relaxant des muscles du squelette tel que l'hydrochlorure de cyclobenzaprine, de manière étendue ou prolongée, ledit relaxant comprenant une ou plusieurs populations de particules contenant des médicaments (billes, pellets, granules, etc.). Au moins une population de billes présente un profil de libération prolongée prédéterminé. Un tel système d'administration de médicaments est adapté à un profil temporel d'administration orale unique de manière à maintenir une concentration de plasma adéquate, soulageant ainsi les spasmes musulaires associés à des états musculo-squelettiques douloureux sur une période de 24 heures.
PCT/US2004/037266 2003-11-14 2004-11-09 Formes posologiques a liberation modifiee de relaxants des muscles du squelette Ceased WO2005048996A2 (fr)

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WO2007010508A3 (fr) * 2005-07-22 2007-09-13 Ranbaxy Lab Ltd Compositions de metaxalone a liberation controlee
US8137734B2 (en) 2008-06-20 2012-03-20 Aptalis Pharmatech, Inc. Preparation of controlled release skeletal muscle relaxant dosage forms
EP2477645B1 (fr) 2009-09-17 2018-08-15 Aptalis Pharma Limited Compositions d'enzyme pancréatique et méthodes pour traiter la pancréatite et l'insuffisance pancréatique

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US9375410B2 (en) 2016-06-28
US20050106247A1 (en) 2005-05-19
US20130209567A1 (en) 2013-08-15
US20090017126A1 (en) 2009-01-15
US9399025B2 (en) 2016-07-26
US20150196505A1 (en) 2015-07-16
US20080124398A1 (en) 2008-05-29
US7544372B2 (en) 2009-06-09
US7829121B2 (en) 2010-11-09
US20150093436A1 (en) 2015-04-02
US20080124399A1 (en) 2008-05-29
US20110217384A1 (en) 2011-09-08
US7387793B2 (en) 2008-06-17
WO2005048996A3 (fr) 2005-09-15
US20160361274A1 (en) 2016-12-15
US7820203B2 (en) 2010-10-26
US20090017127A1 (en) 2009-01-15
US8877245B2 (en) 2014-11-04
US7790199B2 (en) 2010-09-07

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